Microgranules containing cisplatin

ABSTRACT

The invention concerns an oral formulation of cisplatin, in the form of controlled-release microgranules, and its method of formulation by grossing in an aqueous medium. The invention also concerns a pharmaceutical preparation containing controlled-release cisplatin microgranules, optionally combined with an anticancer agent, to be used in anticancer therapy. The invention further provides a use for these microgranules for making orally administered medicaments for polychemotherapy or in combination with radiotherapy.

The present invention relates to a cisplatin formulation for oraladministration.

Cisplatin is an anticancer agent known for its effectiveness but alsofor its significant side effects observed when it is administeredintravenously, in particular: nephrotoxicity, gastrointestinal toxicity(nausea, vomiting), neurotoxicity and moderate myelo-suppression.

The nephrotoxicity induced by cisplatin can be alleviated by intravenoussaline hydration and by diuresis.

For the last twenty-five years, research has been carried out oncisplatin analogues. Only twelve of these analogues have been evaluatedin clinical trials: some have proved to be even more toxic thancisplatin and none has shown an anticancer activity superior tocisplatin.

Researchers have thus turned towards the study of the reduction intoxicity of cisplatin rather than towards that of new analogues.

A first line of research relates to the oral administration of cisplatinin animals.

Studies carried out by Siddik Z. H. et al. and presented at the 74thCongress of the American Cancer Research Association in March 1984allowed the anticancer activity of cisplatin administered by the oralroute in mice affected by plasmacytoma ADJ/PLA to be evaluated. Theplasma platinum concentration reached a peak of 4.3 μg/ml after 30-60minutes for a dose of 50 mg/kg. The bioavailability in the mouse was31-36% and the incidence of nephrotoxicity was only 20%.

Hasegawa Y. et al. confirm with respect to Muridae, in Chem. Pharm.Bull., 33(12), 5511-5514, 1985, that cisplatin passes into the bloodafter oral administration and that it is effective under theseconditions against solid tumours.

Binks S. P. et al. demonstrate, in Biochemical Society Transactions,616th Meeting, London, 14, 694 (1986), that the absorption of cisplatinafter oral administration is so rapid that the plasma platinumconcentration reaches its maximum in less than two hours. The highestlevels of platinum are observed in the kidneys.

Analysis with an electron microscope of tissues excised 48 hours afteroral administration of cisplatin reveals only slight changes in thekidneys, whereas, for an intravenous administration, symptoms ofnephrotoxicity are observable.

Borch R. F. et al. have shown, in Proc. Natl. Acad. Sci., USA, 76,6611-6614, that urea concentrations in the blood were multiplied by 14in rats receiving the maximum tolerated dose of cisplatin via theintravenous route and then this result was confirmed by another study byMorgan S. E. et al. (Pharmacology Communication, 1993, Vol. 3, No. 1,9-18) and shows that administration by the oral route can greatlydecrease the nephrotoxicity of cisplatin. No histopathological change inthe kidneys was observed in mice treated orally with a toxic dose ofcisplatin of 70 mg/kg.

Howell S. B., in Plenum Press, New York. p. 93 (1991), and Harrap K. R.et al., in Adv. Enzyme Regul., 31 (31), 1991, show that the degree ofactivity of cisplatin administered by the oral route is less than thatobtained by the parenteral route and that higher doses are necessary foran oral administration because of the relatively low bioavailability ofcisplatin in this case. Consequently, no clinical trial has been carriedout on man because the bioavailability of cisplatin administered by theoral route was too low in comparison with conventional intravenousformulations.

A second line of research relates to the combination of low doses ofcisplatin with other therapeutic methods.

T. Shirasaka has provided, in Cancer Chemother. Pharmacol., 32, 167-172(1993) and in Jpn. J. Cancer Chemother., 2/(7), 1025-1028 (1994), atherapy which consists in combining the administration of 5-fluorouraciland low-dose cisplatin. He suggests a therapy of four weeks, whichconsists in administering a perfusion of 5-fluorouracil in combinationwith an intravenous dose of 5-6 mg/day of cisplatin.

The anticancer effectiveness of this therapy on the solid tumours of therodents studied is superior to that of 5-fluorouracil alone or ofcisplatin alone and its toxicity is lower.

Many studies carried out in Japan have shown that, with a low-doseregimen, cisplatin in combination with 5-fluorouracil is effective inthe treatment of various cancers; moreover, its toxicity is reduced. Itis then no longer necessary to resort to hydration by an intravenousroute in order to prevent nephrotoxicity.

Moreover, it has been demonstrated, in Chemotherapy, 1996, Vol/Iss/Pg42/6 (452-458), that low-dose cisplatin can also be combined with S1, anantitumour medicament of oral form which is ategafur/5-chloro-2,4-dihydroxypyridine/oxonic acid mixture in a 1/0.4/1molar proportion discovered by T. Shirasaka.

Other combinations of low-dose cisplatin are also possible with otheranticancers, such as, but not restricted to, the combination ofvinblastine with bleomycin, the combination of etoposide with bleomycin,or alternatively paclitaxel.

In addition, Ducreux M. et al., in Annals of Oncology, 5 (Suppl 8), 81(1994), have shown that the combination of radiotherapy and of anadministration of 4-6 mg/m²/day of cisplatin by the intravenous routefor 4-6 weeks improves the anticancer activity and reduces the sideeffects.

There currently exists no oral cisplatin formulation and the object ofthe present invention is to provide controlled-release microgranules fororal administration containing cisplatin, the mean particle size ofwhich is between 0.4 and 1.5 mm, in particular between 1 and 1.25 mm.

Controlled release is understood to mean an instantaneous release, arelease sustained over time or alternatively a release with targeting ofthe absorption site, in particular at the ileum where the pH is of theorder of 7.

This formulation advantageously provides a bioavailability superior tothat of cisplatin of injectable form administered orally and anacceptable gastrointestinal toxicity.

After an intravenous administration, the plasma platinum concentrationincreases and then decreases rapidly, which leads to significantfluctuations in concentration and causes periods of therapeuticunder-and over-concentration responsible for nephrotoxicity andnausea/vomiting.

The controlled-release microgranules formulation according to theinvention advantageously makes it possible to release the activeprinciple more evenly and to avoid plasma peaks while maintaining ablood level which is sufficiently high to produce the desiredtherapeutic effect, without, however, reaching toxic levels which cancause side effects for the patient, because of the extensivedistribution of the granules along the digestive tract.

The formulation according to the invention also makes it possible tokeep the plasma concentration constant over a longer period of time andto decrease the variations between and within individuals by virtue of ahigh exchange surface area and avoids the release of a large amount ofactive principle localized at one point of the digestive mucousmembrane.

An advantage of the oral form according to the invention is that it canbe used by the patient himself in his home; thus, the patient no longerhas to resort to frequent intravenous administrations in a hospitalwhich require professional assistance. Moreover, for hospitalizedpatients, the oral form according to the invention improves the qualityof life by reducing the time spent in hospital and by freeing them frompainful treatments, in particular in the case of perfusions at the rateof 100 hours/week.

Each microgranule according to the invention advantageously comprises animmediate microgranule to which is fixed a coating containing a coatingagent which makes possible the controlled release of cisplatin and/or ofother active principles, the said immediate microgranule being composedeither of a mixture of excipients, of cisplatin and optionally of otheractive principles or of a neutral support grain coated with a mixture ofexcipients, of cisplatin and optionally of other active is principles.

Immediate microgranule is understood to mean a microgranule, theformulation excipients of which have no significant effect on the rateof release or of diffusion of the active principle.

The coating agent which makes possible the controlled release ofcisplatin or optionally of other active principles is preferablycomposed of one or more pharmaceutically acceptable coating polymerschosen in particular from cellulose polymers or from methacrylic acidcopolymers and preferably the poly(ethyl acrylate, methyl methacrylate)ssold under the trade name Eudragit NE 30D®.

The coating containing the coating agent described above isadvantageously composed of a single polymer or optionally of a mixtureof polymers and/or of a sequence of polymer layers.

Various conventional additives can optionally be combined with thepolymer of the coating layer which provides for the controlled release,in particular: a lubricating agent and/or a plasticizing agent and/or asurface-active agent.

The lubricating agent can be composed of a conventional pharmaceuticallyacceptable lubricant, in particular talc.

The plasticizing agent is preferably composed of a pharmaceuticallyacceptable plasticizing agent chosen from aliphatic esters, such asesters of citric, phthalic and oxalic acids, and preferably triethylcitrate.

The surfactant can be of anionic, cationic, amphoteric or, preferably,non-ionic type, in particular the polysorbate 80 sold under the tradename Montanox 80®.

A so-called protective coating or prefixing layer can advantageously beapplied between the immediate microgranule and the coating containingthe coating agent, this inserted layer having the role of isolating theactive principle from the polymer used in the coating described above.

The addition of sodium chloride to the mixture of excipients makes itpossible to reinforce the stability of the cisplatin active principle.The mixture of excipients thus advantageously comprises sodium chloride.

The microgranules according to the invention advantageously contain acisplatin content of between 25 and 350 mg/g and preferably between 50and 60 mg/g.

The present invention also relates to the process for the preparation ofthe controlled-release microgranules containing cisplatin according tothe invention.

The said process consists in fixing cisplatin to neutral support grainsby spraying a fixing suspension containing cisplatin inaqueous/alcoholic medium, in alcoholic medium or in aqueous medium.

The fixing suspension is preferably aqueous and contains a stabilizingagent, such as sodium chloride, and one or more binding agents, such ashydroxypropylmethylcellulose or polyethylene glycol. A surface-activeagent as described above can optionally be added to the fixingsuspension.

The immediate microgranules, once coated with the coating agent whichmakes possible the controlled release of cisplatin, can be lubricatedwith talc.

The solvents used in the stages for the preparation of the microgranulesof the present invention can be aqueous, alcoholic and/oraqueous/alcoholic in nature. Preferably, water will be used as solesolvent during the manufacturing process.

The microgranules according to the invention can be obtained byextrusion-spheronization by mixing, in a single stage, cisplatin,binding agents and stabilizing agents in aqueous medium.

The microgranules described in the present invention are obtained by useof any equipment appropriate for the preparation and the coating ofmicrogranules well known to a person skilled in the art and inparticular equipment of conventional pan, perforated pan, fluidized airbed, extruder and spheronizer type.

Another subject of the present invention is a pharmaceutical preparationcontaining the controlled-release cisplatin microgranules according tothe invention, optionally obtained according to the process describedabove, in an amount which makes it possible to obtain a unit dose ofbetween 10 and 50 mg of cisplatin.

The said pharmaceutical preparation preferably contains a mixture ofcontrolled-release cisplatin microgranules and of an anticancer agent,for example fluorouracil, S1, the combination of vinblastine withbleomycin, the combination of etoposide with bleomycin, or paclitaxel,as combination product for a use in anticancer therapy which issimultaneous, separate or spread out over time.

Finally, the present invention relates to the use of the microgranulesaccording to the invention in manufacturing a medicament, to beadministered by the oral route, intended to be used at low doses, inparticular less than or equal to approximately 20 mg/m²/day.

The said medicament can advantageously be used in polychemotherapyand/or in combination with a radiotherapy in order to obtain an averagecisplatin blood concentration of between 0.5 and 1.0 μg/ml.

The following examples illustrate the invention without limiting thescope thereof. The percentages are expressed by mass, except whenotherwise indicated.

EXAMPLE 1

Protocol for the preparation of immediate microgranules by fixingcisplatin to neutral grains.

Preparation of the Fixing Suspension

The fixing excipients are weighed in the appropriate proportions for anamount of cisplatin of 100 g,

The solvent or the solvent mixture is placed in a container withstirring,

The binder or the mixture of binders is slowly added and the mixture isstirred until a homogeneous solution is obtained,

The active principle is added at the time of fixing and the mixture isstirred until a homogeneous suspension is obtained.

Fixing of the Active Principle to the Neutral Support Grains

The necessary amount of Neutres 20® (sold by the company Np-pharm, themean particle size of which is between 0.7 and 0.9 mm, composed of 75%sucrose and 25% maize starch) is placed in the device used for fixingthe active principle.

The active principle is fixed to the Neutres 20® by continuous sprayingof the suspension described above,

The mass of microgranules obtained is sieved,

The microgranules are pan-dried at ambient temperature.

EXAMPLE 2

Preparation of Immediate Microgranules A

The following fixing excipients are weighed, in the proportions shown,for an amount of cisplatin of 100 g

PEG 4000 18 g 75% of the content on a dry basis PHARMACOAT 603 ®  9 g25% of the content on a dry basis PURIFIED WATER 10 g 5% of the solvent95% ETHYL ALCOHOL 190 g  95% of the solvent

Final formula:

CISPLATIN 22.3%  NEUTRES 20 ® 72.4%  PEG 4000 4.0% PHARMACOAT 603 ® 1.3%THEORETICAL CONTENT 223 mg/g

EXAMPLE 3

Preparation of Immediate Microgranules B

The following fixing excipients are weighed, in the proportions shown,for an amount of cisplatin of 100 g

PEG 4000 18.2 g  30.5% of the content on a dry basis PHARMACOAT 603 ®6.0 g 10.1% of the content on a dry basis SODIUM CHLORIDE 30.2 g  50.7%of the content on a dry basis MONTANOX 80 ® 5.2 g 8.7% of the content ona dry basis PURIFIED WATER 303.0 g  100% of teh solvent

Final formula:

CISPLATIN 5.5% NEUTRES 20 ® 91.3%  PEG 4000 1.0% PHARMACOAT 603 ® 0.3%MONTANOX 80 ® 0.3% SODIUM CHLORIDE 1.6% THEORETICAL CONTENT 55 mg/g

EXAMPLE 4

Preparation of Immediate Microgranules C

The following fixing excipients are weighed, in the proportions shown,for an amount of cisplatin of 100 g

PEG 4000 18.0 g 28.0% of the content on a dry basis PHARMACOAT 603 ® 6.0 g 9.4% of the content on a dry basis SODIUM CHLORIDE 30.0 g 46.7%of the content on a dry basis MONTANOX 80 ® 10.2 g 15.9% of the contenton a dry basis PURIFIED WATER 302.2 g  100% of the solvent

Final formula:

CISPLATIN 5.4% NEUTRES 20 ® 91.0%  PEG 4000 1.0% PHARMACOAT 603 ® 0.3%MONTANOX 80 ® 0.7% SODIUM CHLORIDE 1.6% THEORETICAL CONTENT 54 mg/g

EXAMPLE 5

Preparation of Immediate Microgranules D

The following fixing excipients are weighed, in the proportions shown,for an amount of cisplatin of 100 g

PEG 4000 18.0 g 28.0% of the content on a dry basis PHARMACOAT 603 ® 6.0 g 9.4% of the content on a dry basis SODIUM CHLORIDE 30.0 g 46.7%of the content on a dry basis MONTANOX 80 ® 10.2 g 15.9% of the contenton a dry basis PURIFIED WATER 299.6 g  100% of the solvent

Final formula:

CISPLATIN 5.4% NEUTRES 20 ® 91.0%  PEG 4000 1.0% PHARMACOAT 603 ® 0.3%MONTANOX 80 ® 0.6% SODIUM CHLORIDE 1.7% THEORETICAL CONTENT 54 mg/g

EXAMPLE 6

Preparation of Immediate Microgranules E

The following fixing excipients are weighed, in the proportions shown,for an amount of cisplatin of 100 g

PEG 4000 18 g  72% of the content on a dry basis PHARMACOAT 603 ® 6 g24% of the content on a dry basis SODIUM CHLORIDE 1 g 4% of the contenton a dry basis PURIFIED WATER 240 g  100% of the solvent

Final formula:

CISPLATIN 5.5% NEUTRES 20 ® 93.1%  PEG 4000 1.0% PHARMACOAT 603 ® 0.3%SODIUM CHLORIDE 0.1% THEORETICAL CONTENT 55 mg/g

EXAMPLE 7

Protocol for the Preparation of Sustained release microgranules

Preparation of the Coating Suspension

The coating excipients are weighed in the appropriate proportions,

The solvent or the mixture of solvents is placed in a container withstirring,

The coating agent or the mixture of coating agents is slowly added andthe mixture is stirred until a homogeneous solution is obtained,

The various additives are slowly added and the mixture is stirred untila homogeneous suspension is obtained,

Stirring is continued throughout the coating phase.

Coating the Microgranules

A fraction of the immediate microgranules obtained according to theprotocol of Example 1 is placed in the equipment used for the coating,

The microgranules are coated by continuous spraying of the suspensiondescribed above,

The mass of microgranules obtained is sieved,

The microgranules are dried at ambient temperature,

This sequence of operations is repeated the necessary number of times toproduce the desired kinetics.

EXAMPLE 8

Preparation of Sustained-release Microgranules A1

The following coating excipients are weighed in the proportions shown

EUDRAGIT L 30 D ® 10.0 g  Eudragit ® content on a dry basis = 30% of theweighed mass of Eudragit ® TRIETHYL CITRATE 0.3 g Content on a dry basisof TRIETHYL CITRATE = 10% of content on a dry basis of Eudragit ®PURIFIED WATER 5.0 g Dilution solvent = 50% of the weighed mass ofEudragit ®

The immediate microgranules A of Example 2 are coated

Final formula:

CISPLATIN 18.2%  NEUTRES 20 ® 59.1%  PEG 4000 3.3% PHARMACOAT 603 ® 1.1%EUDRAGIT L 100-55 ® 0.8% EUDRAGIT L 30 D ® 10.2%  EUDRAGIT NE 30 D ®1.0% TRIETHYL CITRATE 1.0% TALC 5.3% THEORETICAL CONTENT 182 mg/g

EXAMPLE 9

Preparation of Sustained-release Microgranules A2

The following coating excipients are weighed in the proportions shown

EUDRAGIT S 100 ® 12.0 g  17 g/l concentrated 6.1 g Content on a drybasis of aqueous ammonia ammonia 0.85% of the solution content on a drybasis on Eudragit ® TRIETHYL CITRATE 6.0 g Content on a dry basis ofTRIETMYL CITRATE = 50% of the content on a dry basis of Eudragit ® TALC4.0 g Content on a dry basis of TALC ⅓ of the content on a dry basis ofEudragit ® PURIFIED WATER 35.9 g  Dilution solvent = 50% of the weighedmass of Eudragit ®

The immediate microgranules A of Example 2 are coated

Final formula:

CISPLATIN 20.7%  NEUTRES 20 ® 67.2%  PEG 4000 3.8% PHARMACOAT 603 ® 1.2%EUDRAGIT S 100 ® 3.77% AMMONIA 0.03%  TRIETHYL CITRATE 1.4% TALC 1.9%THEORETICAL CONTENT 207 mg/g

EXAMPLE 10

Preparation of Sustained-release Microgranules E1

The following coating excipients are weighed in the proportions shown

EUDRAGIT L 30 D ® 10.0 g  Content on a dry basis of Eudragit ®= 30% ofthe weighed mass of Eudragit ® TRIETHYL CITRATE 0.3 g Content on a drybasis of TRIETHYL CITRATE = 10% of the content on a dry basis ofEudragit ® PURIFIED WATER 5.0 g Dilution solvent = 50% of the weighedmass of Eudragit ®

The immediate microgranules E of Example 6 are coated

Final formula:

CISPLATIN 4.5% NEUTRES 20 ® 75.35% PEG 4000 0.8% PHARMACOAT 603 ® 0.3%SODIUM CHLORIDE 0.05% EUDRAGIT L 30 ® 9.0% TRIETHYL CITRATE 0.9% TALC9.1% THEORETICAL CONTENT 45 mg/g

EXAMPLE 11

Preparation of Sustained-release Microgranules E2

The following coating excipients are weighed in the proportions shown

EUDRAGIT NE 30 D ® 10.0 g Content on a dry basis of Eudagit ® = 30% ofthe weighed mass of Eudragit ® PURIFIED WATER  5.0 g Dilution solvent =50% of the weighed mass of Eudragit ®

The immediate microgranules E of Example 6 are coated

Final formula:

CISPLATIN 5.4% NEUTRES 20 ® 91.3% PEG 4000 0.95% PHARMACOAT 603 ® 0.3%SODIUM CHLORIDE 0.05% EUDRAGIT NE 30 D ® 1.0% TALC 1.0% THEORETICALCONTENT 54 mg/g

EXAMPLE 12

Preparation of Sustained-release Microgranules E3

The following coating excipients are weighed in the proportions shown

EUDRAGIT NE 30 10.0 g Content on a dry basis of Eudragit ® = D ® 30% ofthe weighed mass of Eudragit ® PURIFIED WATER  5.0 g Dilution solvent =50% of the weighed mass of Eudragit ®

The immediate microgranules E of Example 6 are coated

Final formula:

CISPLATIN 5.3% NEUTRES 20 ® 89.6% PEG 4000 0.95% PHARMACOAT 603 ® 0.3%SODIUM CHLORIDE 0.05% EUDRAGIT NE 30 D ® 1.9% TALC 1.9% THEORETICALCONTENT 53 mg/g

EXAMPLE 13

Preparation of Sustained-release Microgranules E4

The following coating excipients are weighed in the proportions shown

EUDRAGIT NE 30 10.0 g Content on a dry basis of Eudragit ® = D ® 30% ofthe weighed mass of Eudragit ® TALC  3.0 g Content on a dry basis ofTALC = 100% of the content on a dry basis of Eudragit ® PURIFIED WATER 5.0 g Dilution solvent = 50% of the weighed mass of Eudragit ®

The following coating excipients are weighed in the proportions shown

EUDRAGIT L NE 30 10.0 g Content on a dry basis of Eudragit ® = D ® 30%of the weighed mass of Eudragit ® TALC  3.0 g Content on a dry basis ofTALC = 100% of the content on a dry basis of Eudragit ® TRIETHYL CITRATE 0.3 g Content on a dry basis of TRIETHYL CITRATE = 10% of the contenton a dry basis of Eudragit ® PURIFIED WATER  5.0 g Dilution solvent =50% of the weighed mass of Eudragit ®

The immediate microgranules E of Example 6 are coated

Final formula:

CISPLATIN 4.4% NEUTRES 20 ® 74.8% PEG 4000 0.8% PHARMACOAT 603 ® 0.3%SODIUM CHLORIDE 0.04% EUDRAGIT NE 30 D ® 0.8% EUDRAGIT L 30 D ® 8.56%TRIETHYL CITRATE 0.9% TALC 9.4% THEORETICAL CONTENT 44 mg/g

Preclinical and Clinical Studies

Bioavailability in Animals

The bioavailability of cisplatin microgranules is compared either withthat of cisplatin administered conventionally by the I.V. route(absolute bioavailability) or with that of the injectable formulationadministered by the oral route (relative bioavailability) in the dog,the rat and the monkey after single or repeated administration (1 dailyadministration for 7 days).

Blood samples are taken 15 min, 30 min, 1, 2, 4, 8 and 24 hours afterthe oral or I.V. administration of cisplatin. The total plasma platinumconcentration is determined by spectrophotometric atomic absorption. Themean of the results obtained as regards the absolute bioavailability andthe relative bioavailability are combined in Tables 1 and 2 below.

TABLE 1 ABSOLUTE BIOAVAILABILITY IV CDDP administered by the oral A A1route E2 E3 Dog − n = 3 63.4% 46.0% 47.3% 66.1% 49.0% 1 mg/kg (20 mg/m²)Monkey − n = 3 17.3% 11.4%  8.0% 13.7%  7.7% 1 mg/kg Rat − n = 3 47.7%41.9% 44.2% 1 mg/kg (6 mg/m²)

TABLE 2 RELATIVE BIOAVAILABILITY WITH RESPECT TO THE INJECTABLEFORMULATION ADMINISTERED PER OS IN THE RAT E E1 E2 E3 E4 Singleadministration 117% 118% 138%  69% 163% 2 mg/kg (12 mg/m²) n = 4Repeated administra- 173% 249% 206% 164% 128% tion 0.5 mg/kg/day (3mg/m²/day) for 7 days n = 5

Moreover, the residual plasma cisplatin concentrations are measured inthe rat after administration of the formulations described in thepresent invention, in comparison with the injectable formulationadministered per os, at the rate of 2 mg/kg/day (12 mg/m²/day) for 7consecutive days with a single daily intake. The results are illustratedby the curves presented in the appendix, FIGS. 1 and 2.

FIG. 1 represents the plasma cisplatin concentration, as a function oftime, of five groups of five rats to which have been respectivelyadministered 2 mg/kg/day (12 mg/m²/day) of microgranules E, E2, E3 andE4 by the oral route and injectable cisplatin administered per os for 7consecutive days at the rate of a single intake per day. The plasmacisplatin concentration is measured 24 hours after each administration.

FIG. 2 represents the plasma cisplatin concentration, as a function oftime, of three groups of five rats to which have been respectivelyadministered microgranules B and C by the oral route and injectablecisplatin administered per os under the same conditions as those in FIG.1.

These combined results show that:

the digestive absorption of the cisplatin microgranule oral formulationsaccording to the invention is superior to that of the injectableformulation administered per os in all the species tested, whether aftersingle or repeated administration,

the plasma platinum concentrations measured after administration of thecisplatin microgranules according to the invention are more sustainedthan those obtained after oral administration of an equivalent dose ofan injectable formulation.

Acute Toxicology and Histopathology in Dogs of the Beagle Breed Treatedwith Microgranules E2

The objective of this study is to determine the maximum tolerated dose(MTD) of cisplatin microgranules E2 in the dog after the administrationof a single dose. A total of 6 male dogs and 6 female dogs is used.Doses of 0.2, 0.5, 1.0 and 2.0 mg/kg (4, 10, 20 and 40 mg/m²) ofcisplatin microgranules by the oral route and a dose of 1 mg/kg (20mg/m²) of cisplatin of trademark Cisplatyl® by the intravenous route areadminis-tered to the animals.

The plasma platinum concentration is measured 30 min, 1, 4 and 24 hoursafter administration. Histopathological examination is carried out atthe end of the 14th day

The animals to which 1 or 2 mg/kg (20 or 40 mg/m²) of cisplatinmicrogranules and 1 mg/kg of I.V. cisplatin have been administeredsuffered from vomiting. Cases of diarrhoea were recorded in the animalstreated with 1 mg/kg of I.V. cisplatin and 2 mg/kg of cisplatinmicrogranules. The 2 mg/kg oral dose of cisplatin microgranules alsocaused a loss in weight, a decrease in food intake, a decrease in weightof the spleen and thymus, a duodenal ulcer in one dog and slight renallesions.

Histopathological examination shows that virtually all the animalstreated with 1.0 mg/kg and 2.0 mg/kg of cisplatin microgranules sufferfrom moderate hypoplasia of the bone marrow. Intensity of hypoplasiadepends on the dose of cisplatin administered.

The 1 mg/kg oral dose of cisplatin microgranules induces toxic effectsto a lesser extent than the 1 mg/kg dose of I.V. cisplatin. Moreover,these toxic effects are not irreversible.

The lower doses of cisplatin microgranules administered by the oralroute are particularly well tolerated and only changes of littleimportance are noticed in the intestine.

The maximum tolerated dose (MTD) of cisplatin microgranules E2 in thedog after administration of a single dose thus lies between 1.0 mg/kgand 2.0 mg/kg. The absolute bioavailability of platinum lies between 41and 77% (mean 64%). Moreover, the inter-animal variability is very lowas regards the maximum plasma concentrations.

Subacute Toxicology in Dogs of the Beagle Breed After Administration ofRepeated Doses of Cisplatin Microgranules E2

Zero (empty hard gelatin capsules, 0.25 and 1.0 mg/kg/day doses ofcisplatin microgranules are administered to male dogs (3 per group) overa period of 4 weeks.

The weight of the dogs is monitored twice weekly and food and waterintake is checked once weekly. Biochemical and haematologicalexaminations of the blood and of the urine are carried out before andafter the experimentation. The blood platinum concentrations aremeasured once weekly by spectrometric atomic absorption.

Histopathological and macroscopic examination is carried out at the endof the experimentation.

In the 1.0 mg/kg (20 mg/m²) group:

The autopsy shows haemorrhagic lesions of the pylorus, of the duodenumand of the ileocaecal region of the colon.

Histopathological examination shows that virtually all the animalstreated with 1.0 mg/kg of cisplatin microgranules suffer from pronouncedhypoplasia of the bone marrow, from erosion in the gastrointestinalregion, from granular degeneration of the renal tubules and fromnecrotic lesions of the testicles.

In the 0.25 mg/kg (5 mg/m²) group

General tolerance is satisfactory throughout the duration of thetreatment, with a slight reduction in food intake. Histopathologicalexamination reveals a slight hypoplasia of the bone marrow.

Absolute Bioavailability in Man of Microgranules E2

Eight patients suffering from cancer of such a nature as to be sensitiveto cisplatin receive, under randomization conditions, a single dose of10 mg/m² of cisplatin, either orally in the form of microgranules E2(hard gelatin capsules containing 2.5 and 5 mg) or by intravenousperfusion for 30 minutes (Cisplatyl® Bellon).

The total plasma platinum levels are measured before administration ofthe medicaments and then 15 min, 30 min, 45 min, 1h, 1h 30, 2h, 4h, 8h,12h and 24h after administration of the medicaments.

Eight patients received the microgranules E2 and eight other patientsreceived Cisplatyl® Bellon by the intravenous route. The mean value ofthe absolute bioavailability of cisplatin microgranules E2 is 39%. Thevariability between individuals after administration of microgranules E2is moderate and similar to that observed after administration of I.V.Cisplatyl® (CV% =27.4% p.o. and 23.7% I.V. respectively).

What is claimed is:
 1. Controlled-release microgranules comprising (1)(a) a mixture comprising cisplatin and at least one pharmaceuticallyacceptable excipient or (b) a core of a neutral support grain coatedwith a mixture comprising cisplatin and at least one pharmaceuticallyacceptable excipient; and (2) a coating fixed to the microgranule,wherein the coating comprises a coating agent which enables thecontrolled release of the mixture; wherein the microgranules have a meanparticle size of between 0.4 and 1.5 mm; and wherein the microganulescontain only cisplatin as an active ingredient.
 2. Thecontrolled-release microgranules of claim 1, wherein the coating agentis a cellulose polymer or a methacrylic acid polymer.
 3. Thecontrolled-release microgranules of claim 2, wherein the coating agentis a poly(ethyl acrylate, methyl acrylate).
 4. The controlled-releasemicrogranules of claim 1, wherein the coating agent consists of a singlepolymer, or a mixture of polymers.
 5. The controlled-releasemicrogranules of claim 1, wherein the coating comprises one or morepolymer layers.
 6. The controlled-release microgranules of claim 1,wherein the coating further comprises a lubricating agent combined withthe coating agent.
 7. The controlled-release microgranules of claim 6,wherein the lubricating agent is talc.
 8. The controlled-releasemicrogranules of claim 1, wherein the coating further comprises aplasticizing agent combine with the coating agent.
 9. Thecontrolled-release microgranules of claim 8, wherein the plasticizingagent is triethyl citrate.
 10. The controlled-release microgranules ofclaim 1, wherein the coating further comprises a surface active agentcombined with the coating agent.
 11. The controlled-releasemicrogranules of claim 10, wherein the surface active agent ispolysorbate
 80. 12. The controlled-release microgranules of claim 1,wherein the coating further comprises a lubricating agent, aplasticizing agent, and a surface active agent combined with the coatingagent.
 13. The microgranules of claim 1, further comprising a protectivecoating layer fixed in between the microgranule core and the coating.14. The controlled-release microgranules of claim 1, wherein theexcipient comprises sodium chloride.
 15. The controlled-releasemicrogranules of claim 1, having a cisplatin content of between 25 and350 mg of cisplatin per gram of microgranules.
 16. Thecontrolled-release microgranules of claim 15, wherein the cisplatincontent is between 50 and 60 mg of cisplatin per gram of microgranules.17. A process for preparing the microgranules of claim 1, whichcomprises spraying cisplatin in a suspension medium onto a neutralsupport grain to form microgranules, and then fixing a coating to themicrogranules, wherein the suspension medium is water, an alcohol, or awater-alcohol mixture.
 18. The process of claim 17, wherein thesuspension medium further comprises a stabilizing agent, a bindingagent, and a surface active agent.
 19. The process of claim 18, whereinthe stabilizing agent is sodium chloride.
 20. The process of claim 18,wherein the binding agent is hydroxypropylmethylcellulose orpolyethylene glycol.
 21. The process of claim 18, wherein themicrogranule is coated with a coating agent.
 22. The process of claim18, wherein the coating further comprises a lubricating agent combinedwith the coating agent.
 23. The process of claim 22, wherein thelubricating agent is talc.
 24. A pharmaceutical composition comprising amicrogranule according to claim 1, having a unit dose of between 10 and50 mg.
 25. A method for manufacturing an oral medicament, comprisingpreparing microgranules according to claim 1 and formulating an oralmedicament comprising said microgranules.
 26. A method for treatingcancer comprising administering to a subject in need thereof the oralmedicament according to claim 25 at a daily cisplatin dosage of not morethan 20 mg/m².
 27. The method according to claim 26, in combination withadministering to the subject at least one other chemotherapy agent. 28.A method for treating cancer comprising administering to a subject inneed thereof the oral medicament according to claim 26, in combinationwith a radiotherapy treatment.
 29. The method according to claim 26,wherein the average blood cisplatin concentration of said patient ismaintained at a level between 0.5 and 1.0 μg/ml.
 30. Thecontrolled-release microgranules of claim 1, wherein the mean particlesize of said microgranules is between 1 and 1.25 mm.